Quaternary ammonium compounds

ABSTRACT

The invention features quaternary ammonium compounds of formula I, described herein, and their use in treating asthma, chronic obstructive pulmonary disorder, allergic rhinitis, and infectious rhinitis.

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. ProvisionalApplication Serial No. 60/421,417 filed on Oct. 25, 2002, under 35 USC119(e)(i).

TECHNICAL FIELD

[0002] The present invention concerns a novel class of quaternaryammonium compounds, pharmaceutical compositions containing the same, thecompounds for use as medicaments, and use of the compounds for themanufacture of specific medicaments. The present invention also concernsa method of treatment involving administration of the compounds. Thenovel compounds are useful as antimuscarinic agents. In particular, thenovel compounds are useful for the treatment of asthma, a group ofbreathing disorders termed Chronic Obstructive Pulmonary Disease (COPD),allergic rhinitis, and infectious rhinitis.

BACKGROUND OF THE INVENTION

[0003] “Asthma” refers to a chronic lung disease causingbronchoconstriction (narrowing of the airways) due to inflammation(swelling) and tightening of the muscles around the airways. Theinflammation also causes an increase in mucus production, which causescoughing that may continue for extended periods. Asthma is generallycharacterized by recurrent episodes of breathlessness, wheezing,coughing, and chest tightness, termed exacerbations. The severity ofexacerbations can range from mild to life threatening. The exacerbationscan be a result of exposure to e.g. respiratory infections, dust, mold,pollen, cold air, exercise, stress, tobacco smoke, and air pollutants.

[0004] “COPD” refers to Chronic Obstructive Pulmonary Disease, primarilyassociated with past and present cigarette smoking. It involves airflowobstruction, mainly associated with emphysema and chronic bronchitis.Emphysema causes irreversible lung damage by weakening and breaking theair sacs within the lungs. Chronic Bronchitis is an inflammatorydisease, which increases mucus in the airways and bacterial infectionsin the bronchial tubes, resulting in obstructed airflow.

[0005] “Allergic rhinitis” refers to acute rhinitis or nasal rhinitis,including hay fever. It is caused by allergens such as pollen or dust.It may produce sneezing, congestion, runny nose, and itchiness in thenose, throat, eyes, and ears.

[0006] “Infectious rhinitis” refers to acute rhinitis or nasal rhinitisof infectious origin. It is caused by upper respiratory tract infectionby infectious rhinoviruses, coronaviruses, influenza viruses,parainfluenza viruses, respiratory syncytical virus, adenoviruses,coxsackieviruses, echoviruses, or Group A beta-hemolytic Streptococciand generically referred to as the common cold. It may produce sneezing,congestion, runny nose, and itchiness in the nose, throat, eyes, andears.

SUMMARY OF THE INVENTION

[0007] In one aspect, the invention features quaternary ammoniumcompounds of formula I

[0008] and any stereoisomers thereof, wherein

[0009] R₁ is selected from C₁-C₆ alkyl, —CH₂—(C₁-C₄ alkenyl), and—CH₂—(C₁-C₆ alkynyl), each of which is optionally substituted with agroup selected from phenyl, C₁-C₄ alkoxy, and hydroxyl; and

[0010] X represents an anion of a pharmaceutically acceptable acid.

[0011] Embodiments of this aspect of the invention may include one ormore of the following. X is selected from the group consisting of theanions of the following acids: tartaric, hydrochloric, hydrobromic,hydroiodic, sulfuric, phosphoric, nitric, citric, methanesulfonic,CH₃—(CH₂)_(n)—COOH where n is 0-4, HOOC—(CH₂)n—COOH where n is 1-4,HOOC—CH═CH—COOH, and benzoic. X is selected from the group consisting ofiodide, bromide, and chloride. The compound is(3S)-3-(2-amino-2-oxo-1,1-diphenylethyl)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]-1-methylpyrrolidiniumiodide.

[0012] In another aspect the invention features a pharmaceuticalcomposition including a therapeutically effective amount of a quaternaryammonium compound of formula I. The pharmaceutical composition mayinclude a suitable pharmaceutical carrier.

[0013] In another aspect the present invention also provides aquaternary ammonium compound of formula I for use as a medicament. Thepresent invention also includes using a quaternary ammonium compound offormula I for the manufacture of a medicament for treating asthma,chronic obstructive pulmonary disease (COPD), allergic rhinitis, andinfectious rhinitis.

[0014] In yet another aspect, the invention provides a method oftreating asthma, chronic obstructive pulmonary disease (COPD), allergicrhinitis, or infectious rhinitis in a mammal, including man, comprisingadministering to said mammal, in need of such a treatment, atherapeutically effective amount of a quaternary ammonium compound offormula I.

[0015] Advantageously, the quaternary ammonium compounds of formula Iunexpectedly exhibit prolonged efficacy as an antimuscarininc agent whencompared to tertiary amine, e.g., non-quaternized, forms of thecompounds.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1 is a plot illustrating the average enhanced pause (lungresistance) determined ten minutes after administering, via inhalation,a compound of formula I to Balb/c mice.

[0017]FIG. 2 is a plot illustrating the average enhanced pause (lungresistance) determined 36 hours after administering, via inhalation, acompound of formula I to Balb/c mice.

[0018]FIGS. 3A, 3B, and 3C are plots illustrating the lung resistance ofa quaternary ammonium compound of the invention relative to the tertiaryamine form of the compound at varying concentrations.

DESCRIPTION OF THE INVENTION

[0019] In describing the preferred embodiment, certain terminology willbe utilized for the sake of clarity. Such terminology is intended toencompass the recited embodiments, as well as all technical equivalentsthat operate in a similar manner for a similar purpose to achieve asimilar result. To the extent that any pharmaceutically active compoundis disclosed or claimed, it is expressly intended to include all activemetabolites produced in vivo, and, is expressly intended to include allenantiomers, isomers or tautomers where the compound is capable of beingpresent in its enantiomeric, isomeric or tautomeric form. Allstereoisomers have useful activity. Therefore, the invention includesuse of each stereoisomer separately, as well as mixtures thereof.

[0020] The compounds of formula I can be prepared by one skilled in theart. The quaternary ammonium compounds of formula I may be prepared bymeans, well known to those skilled in the art, for preparing quaternaryammonium compounds from tertiary amines. For instance, the quaternaryammonium compounds may be produced by alkylating the pyrrolidinetertiary nitrogen using the tertiary amines of U.S. Pat. No. 5,096,890,the contents of which are hereby incorporated by reference, and otherknown compounds as starting materials.

[0021] The general term “quaternary ammonium compound” relates to anycompound that can be regarded as derived from ammonium hydroxide or anammonium salt by replacement of all four hydrogen atoms of the NH₄-ionby organic groups. The specific compounds are for nomenclature reasons(see e.g. Chemical Abstracts) named as “aminium” compounds, but it ispossible to use the term “ammonium” in the names. For example,(3R)-3-(2-hydroxy-s-methylphenyl)-N,N-diisopropyl-N-methyl-3-phenylpropanylaminium bromide can also be named as an ammonium compound:(3R)-[3-(2-hydroxy-s-methylphenyl)-3-phenylpropyl]diisopropylmethylammonium bromide.

[0022] By way of example, a tertiary amine according to U.S. Pat. No.5,096,890, or its salt, is dissolved in a suitable solvent. The tertiaryamine is allowed to react with an organic substrate, e.g. an organichalide. The substrate contains a C₁-C₆ alkyl, preferably a C₁-C₃ alkyl,optionally substituted with phenyl, and a leaving group. The identity ofthe leaving group is not critical, but it is preferred that the leavinggroup is a halide, such as iodide or bromide. Thus, exemplary substratesinclude methyl iodide, methyl bromide, ethyl iodide, propyl iodide,benzyl bromide or benzyl iodide. The resulting reaction product is aquaternary ammonium compound, which is readily crystallized in suitablesolvents, known to those skilled in the art. The crystals thus producedare quaternary ammonium salts. Their identity is confirmed by standardmethods, such as melting point determination, nuclear magnetic resonance(NMR) analysis and mass spectrometry.

[0023] The compounds of the invention are preferably administered asquarternary ammonium salts which include counter ions. X represents theanion, e.g., the counter ion, of a pharmaceutically acceptable acid. Forinstance X may be selected from the following anions: tartrate,chloride, bromide, iodide, sulfate, phosphate(s), nitrate, citrate,methanesulfonate, carboxylates with from two to six carbon atoms,dicarboxylates with from two to six carbon atoms, maleate, fumarate, andbenzoate. For other acceptable quarternary ammonium salts, see Int. J.Pharm., 33, 201-217 (1986). Particularly preferred ions are chloride,iodide and bromide, especially bromide and iodide.

[0024] The substituent R₁ is selected from the group including C₁-C₆alkyl, straight or branched, optionally substituted with 1-2 of phenylor hydroxyl, or both. Thus, R₁ independently represent methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, orisohexyl, optionally substituted with 1-2 of phenyl or hydroxyl, orboth. It is particularly preferred that R₁ represents methyl or ethyl,preferably methyl.

[0025] The compounds according to the present invention areantimuscarinic agents. “Antimuscarinic agents” refer to muscarinicreceptor antagonists. Examples of known antimuscarinic agents includetolterodine, hydroxytolterodine, 2-(diisopropylamino)ethyl-1-phenylcyclopentanecarboxylate, propiverine, oxybutynin,trospium, temiverine, and ipratropium.

[0026] Propiverine is 1-methyl-4-piperidyl .alpha., .alpha.-diphenyl-.alpha.-(n-propoxy)acetate and is disclosed in East GermanPatent 106,643 and in CAS 82-155841s (1975). Oxybutynin is4-(diethylamino)-2-butynylalphaphenylcyclohexaneglycolate and isdisclosed in UK Patent 940,540. Trospium is 3alpha-hydroxyspiro[lalphaH, SalphaH-nortropane30 8,1′pyrrolidinium]chloride benzilate andis disclosed in U.S. Pat. No. 3,480,623. Temiverine is 3S benzeneaceticacid, .alpha.-cyclohexyl-alpha.-hydroxy-,4-(diethylamino)-1,1-dimethyl-2-butynyl ester and is disclosed in U.S.Pat. No. 5,036,098. Ipratropium is 8-isopropylnoratropine methobromideand is disclosed in U.S. Pat. No. 3,505,337.

[0027] The compounds of formula I have anti-cholinergic properties andunexpectedly exhibit prolonged activity in the lung. Thus, the compoundsof formula I are useful for the treatment of acetylcholine-mediateddisorders. In particular, the compounds of are useful for treatingasthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis,and infectious rhinitis.

[0028] The compounds of the present invention are used to treat mammals,including man and horse. It is preferred that the mammal is a human. Thecompounds according to the invention, in the form of free base or saltswith pharmaceutically acceptable acids, or solutions thereof, can bebrought into suitable dosage forms, such as compositions foradministration through the oral, rectal, transdermal, parenteral, nasal,or pulmonary route in accordance with accepted pharmaceuticalprocedures. In particular, the compositions may be administered viainhalation or insufflation. Such pharmaceutical compositions accordingto the invention comprise the compounds according to the invention inassociation with compatible pharmaceutically acceptable carriermaterials, or diluents, as is well known in the art. The carriers may beany inert material, organic or inorganic, suitable for administration,such as: water, gelatin, gum arabicum, lactose, microcrystallinecellulose, starch, sodium starch glycolate, calcium hydrogen phosphate,magnesium stearate, talcum, colloidal silicon dioxide, and the like.Such compositions may also contain other pharmaceutically active agents,and conventional additives such as stabilizers, wetting agents,emulsifiers, flavoring agents, buffers, binders, disintegrants,lubricants, glidants, antiadherents, propellants, and the like. Thecarrier, e.g., non-active ingredient, can be just (sterile) water withthe pH adjusted to where the active pharmaceutical agent is verysoluble. It is preferred that the pH be at or near 7. Alternatively andpreferably, the non-active carrier agent should be physiological salinewith the pH adjusted appropriately.

[0029] The novel compounds according to the present invention can beadministered in any suitable way. The compounds according to theinvention can be made up in solid or liquid form, such as tablets,capsules, powders, syrups, elixirs and the like, aerosols, sterilesolutions, suspensions or emulsions, and the like. The compounds areadvantageously administered via inhalation or insufflation. When theadministration form is inhalation or insufflation, the compounds arepreferably in the form of either an aerosol or a powder.

[0030] The term “effective amount” refers to a therapeutically effectiveamount for treating asthma, chronic obstructive pulmonary disease(COPD), allergic rhinitis, or infectious rhinitis. The terms “therapy”and “therapeutically” encompass all kinds of treatments, includingprophylaxis. In particular, “therapeutically effective” means that it iseffective for anticholinergic treatment.

[0031] For purposes of illustration, dosages are expressed for based onthe inhalation of an aerosol solution, such as the product AtroventInhalation Aerosol (Boehringer Ingelheim). Adjustments in dosages foradministration by other modes of inhaled administration are well knownto those skilled in the art.

[0032] In general, a therapeutically effective amount of antimuscarinicagent is from about 1 μg to about 1,000 μg, e.g., from about 10 μg toabout 1,000 μg or from about 100 μg to about 1000 μg. However, the exactdosage of the specific compound according to the invention will varydepending on its potency, the mode of administration, the age and weightof the patient and the severity of the condition to be treated. Thedaily dosage may, for example, range from about 0.01 μg to about 10 μgper kg of body weight, administered singly or multiply in doses e.g.from about 1 μg to about 1,000 μg each. The compounds of formula I canbe administered from one to four times daily, e.g., once or twice daily.

[0033] The dosage form for inhalation can be an aerosol. The minimumamount of an aerosol delivery is about 0.2 ml and the maximum aerosoldelivery is about 5 ml. The concentration of the compounds according tothe invention may vary as long as the total amount of spray delivered iswithin the about 0.2 to about 5 ml amount and it delivers atherapeutically effective amount of the compound of formula I. It iswell known to those skilled in the art that if the concentration ishigher, one gives a smaller dose to deliver the same effective amount.

[0034] The dosage form for inhalation can also be via intranasal spray.The minimum amount of an aerosol delivery is about 0.02 ml per nostriland the maximum aerosol delivery is about 0.2 ml per nostril. Theconcentration of the compounds according to the invention may vary aslong as the total amount of spray delivered is within about 0.02 ml pernostril to about 0.2 ml per nostril, e.g., between about 0.05 ml pernostril and about 0.08 ml per nostril, and it delivers a therapeuticallyeffective amount of the compound of formula I.

[0035] Of course, the volume of aerosol or intranasal spray fordelivering a therapeutically effective amount of the compound of formulaI depends upon the concentration of the compound in the aerosol orintranasal spray, e.g., higher concentrations of the compound of formulaI require smaller dosage volumes to deliver a therapeutically effectiveamount and lower concentrations of the compound of formula I requirelarger dosage volumes to deliver the same therapeutically effectiveamount.

[0036] Aerosols for inhalation of various pharmaceutical agents are wellknown to those skilled in the art, including many aerosols for treatingasthma. Aerosols may be produced with a nebulizer. Typically, thenebulizer is charged with a carrier solution and the compound of formulaI in an amount sufficient to effectively deliver a therapeuticallyeffective amount of the antimuscarininc compound. For instance,depending upon the nebulizer and its operating conditions, the nebulizermay be charged with several hundred mg of antimuscarinic compound inorder to deliver about 1 μg to about 1000 μg, e.g., from about 10 μg toabout 1000 μg or from about 50 μg to about 500 μg, of the compound offormula I.

[0037] The dosage form for inhalation may also be in powder form.Powders for inhalation of various pharmaceutical agents are well knownto those skilled in the art, including many powders for treating asthma.When the dosage form is a powder, the compounds according to theinvention can be administered in pure form or diluted with an inertcarrier. When an inert carrier is used, the compounds according to theinvention are compounded such that the total amount of powder delivereddelivers an “effective amount” of the compounds according to theinvention. The actual concentration of the active compound may vary. Ifthe concentration is lower, then more powder must be delivered, if theconcentration is higher, less total material must be delivered toprovide an effective amount of the active compound according to theinvention.

[0038] Pharmaceutically acceptable refers to those properties and/orsubstances which are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

EXAMPLES

[0039] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, practice the presentinvention to its fullest extent. The following detailed examplesdescribe how to prepare the various compounds and/or perform the variousprocesses of the invention and are to be construed as merelyillustrative, and not limitations of the preceding disclosure in any waywhatsoever. Those skilled in the art will promptly recognize appropriatevariations from the procedures both as to reactants and as to reactionconditions and techniques.

[0040] All temperatures are in degrees Celsius. Ether refers to diethylether. Physiological saline refers to a 0.9% aqueous 5 sodium chloridesolution. When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v). When the solubility of a solid in a solvent is usedthe ratio of the solid to the solvent is weight/volume (wt/v).

Example I Production of(3S)-3-(2-amino-2-oxo-1,1-diphenylethyl)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]-1-methylpyrrolidiniumiodide

[0041](3S)-3-(2-amino-2-oxo-1,1-diphenylethyl)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]-1-pyrrolidine(1) is prepared according to the procedures described in U.S. Pat. No.5,096,890. To COMPOUND (1), free base in toluene, is added methyl iodide(1 ml). Acetonitrile (5 ml) is added to the mixture and stirred overnight at 20-25° C. The solvent is removed by blowing dry nitrogen.Acetone (1 ml) and hexane (2 ml) are added and the mixture is filteredat 20-25° C. to give the title compound. The identity of the compoundhas been further verified and characterized by NMR analysis, massspectrometry, and melting point determination.

Example II Bronchodilatory Effect of Inhaled Quaternary Ammonium Saltsin Balb/c Mice

[0042] Female BALB/c mice, weight range 19-22 g, were obtained fromCharles P.iver Laboratories (Kingston, N.C.). They received food andwater ad libitum. All procedures in these studies were in compliancewith the Animal Welfare Act P.egulation, 9CFP. Parts 1 and 2,Publication (NIH) 85-23, 1985.

[0043] Compounds for aerosol administration were prepared in sterileDulbecco's Phosphate Buffered Saline. Mice were placed in acarousel-style, nose only, exposure chamber and allowed to inhaleaerosols for five minutes, using an ICN SPAG-2 nebulizer. This nebulizergenerates a mean aerosol particle size of 1.3 microns at a rate ofapproximately 0.25 ml/minute.

[0044] Ten minutes and 36 hours later, the mice were moved to whole bodyplethysmograph chambers. Bronchoconstriction was induced in mice byadministration of an 80 mg/ml methacholine (MC) aerosol into theplethysmograph chambers for 5 minutes. The mice were allowed to inhalean aerosol containing 80 mg/ml methacholine following inhalationtreatment with DPBS vehicle (Dulbecco's Phosphate Buffered Saline), or80 mg/ml methacholine following inhalation treatment with 1.29 mg/ml of(3S)-3-(2-amino-2-oxo-1,1-diphenylethyl)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]-1-methylpyrrolidiniumiodide. The average enhanced pause (Penh, lung resistance),corresponding to airflow resistance, was determined and statisticallyanalyzed using Kruskal-Wallis one way ANOVA. In order to determine thebaseline, saline aerosol (without methacholine) was also separatelyadministered to the mice.

[0045] Referring to FIG. 1, Inhalation of the title compound resulted in100% inhibition of the bronchoconstriction to methacholine when measured10 minutes after dosing with the title compound. FIG. 2 shows a 61%inhibition of the bronchoconstriction to methacholine when measured 36hours after dosing with the compound of example I.

[0046] Referring to FIGS. 3A-3C, the efficacy of the compound of exampleI, a quaternary ammonium compound, is compared to its tertiary amineform at varying concentrations. The compound of example I exhibitsextended activity as compared to the tertiary amine form even at higherdosages of the tertiary amine.

1. A quaternary ammonium compound of formula I

and any stereoisomers thereof, wherein R₁ is selected from C₁-C₆ alkyl,—CH₂—(C₁-C₄ alkenyl), and —CH₂—(C₁-C₆ alkynyl), each of which isoptionally substituted with a group selected from phenyl, C₁-C₄ alkoxy,and hydroxyl, and X represents an anion of a pharmaceutically acceptableacid.
 2. The compound of claim 1, wherein X is selected from the groupconsisting of the anions of the following acids: tartaric, hydrochloric,hydrobromic, hydroiodic, sulfuric, phosphoric, nitric, citric,methanesulfonic, CH₃—(CH₂)_(n)—COOH where n is 0-4, HOOC—(CH₂)n—COOHwhere n is 1-4, HOOC—CH═CH—COOH, and benzoic.
 3. The compound of claim1, wherein X is selected from the group consisting of iodide, bromide,and chloride.
 4. The compound of claim 1, wherein X is iodide.
 5. Thecompound of claim 1, wherein X is bromide.
 6. The compound of claim 1,wherein X is chloride.
 7. The compound of claim 1, wherein R₁ is methyl.8. A compound(3S)-3-(2-amino-2-oxo-1,1-diphenylethyl)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]-1-methylpyrrolidiniumiodide.
 9. A pharmaceutical composition comprising a therapeuticallyeffective amount of a quaternary ammonium compound of formula I

and any stereoisomers thereof, wherein R₁ is selected from C₁-C₆ alkyl,—CH₂—(C₁-C₄ alkenyl), and —CH₂—(C₁-C₆ alkynyl), each of which isoptionally substituted with a group selected from phenyl, C₁-C₄ alkoxy,and hydroxyl; and X represents an anion of a pharmaceutically acceptableacid.
 10. The pharmaceutical composition of claim 9, wherein thepharmaceutical composition further comprises a suitable pharmaceuticalcarrier.
 11. A method of treating asthma in a mammal, comprisingadministering a therapeutically effective amount of a quaternaryammonium compound of formula I to a mammal in need of such a treatment,wherein the compound of formula I has the structure

and any stereoisomers thereof, wherein R₁ is selected from C₁-C₆ alkyl,—CH₂—(C₁-C₄ alkenyl), and —CH₂—(C₁-C₆ alkynyl), each of which isoptionally substituted with a group selected from phenyl, C₁-C₄ alkoxy,and hydroxyl; and X represents an anion of a pharmaceutically acceptableacid.
 12. A method of treating chronic obstructive pulmonary disease ina mammal, comprising administering a therapeutically effective amount ofa quaternary ammonium compound of formula I to a mammal in need of sucha treatment, wherein the compound of formula I has the structure

and any stereoisomers thereof, wherein R₁ is selected from C₁-C₆ alkyl,—CH₂—(C₁-C₄ alkenyl), and —CH₂—(C₁-C₆ alkynyl), each of which isoptionally substituted with a group selected from phenyl, C₁-C₄ alkoxy,and hydroxyl; and X represents an anion of a pharmaceutically acceptableacid.
 13. A method of treating allergic rhinitis in a mammal, comprisingadministering a therapeutically effective amount of a quaternaryammonium compound of formula I to a mammal in need of such a treatment,wherein the compound of formula I has the structure

and any stereoisomers thereof, wherein R₁ is selected from C₁-C₆ alkyl,—CH₂—(C₁-C₄ alkenyl), and —CH₂—(C₁-C₆ alkynyl), each of which isoptionally substituted with a group selected from phenyl, C₁-C₄ alkoxy,and hydroxyl; and X represents an anion of a pharmaceutically acceptableacid.
 14. A method of treating infectious rhinitis in a mammal,comprising administering a therapeutically effective amount of aquaternary ammonium compound of formula I to a mammal in need of such atreatment, wherein the compound of formula I has the structure

and any stereoisomers thereof, wherein R₁ is selected from C₁-C₆ alkyl,—CH₂—(C₁-C₄ alkenyl), and —CH₂—(C₁-C₆ alkynyl), each of which isoptionally substituted with a group selected from phenyl, C₁-C₄ alkoxy,and hydroxyl; and X represents an anion of a pharmaceutically acceptableacid.